Cardiovascular effects of 1,5-benzothiazepine derivatives having a l-cis and d-cis configuration in anesthetized dogs.
TA-993, a new 1,5-benzothiazepine derivative having a l-cis configuration, has a selective increasing action on limb blood flow, in addition to an antiplatelet aggregating action. The cardiovascular action of TA-993 is quite different from diltiazem, which is a well-known 1,5-benzothiazepine derivative having a d-cis configuration. Therefore, we compared the cardiovascular actions of d-cis and l-cis isomers of TA-993 with those of diltiazem. l-cis-Diltiazem, as well as TA-993, progressively increased femoral, brachial and common carotid blood flow with little change in arterial pressure or vertebral blood flow. However, the peak response to l-cis-diltiazem (20 min after the administration) was observed earlier than that to TA-993 (60 min after the administration). On the other hand, d-cis-TA-993, as well as diltiazem, caused transient hypotension, tachycardia and increases in vertebral, brachial, femoral and common carotid blood flow. Furthermore, their peak effects were observed immediately after the administration. Potency ratios of the vasorelaxing effects of TA-993, l-cis-diltiazem and d-cis-TA-993 to diltiazem in the isolated and K+-contracted canine femoral artery were 0.096, 0.032 and 1.209, respectively. pA2 values for TA-993 and diltiazem against Ca2+-induced contractions in the isolated and K+-depolarized canine saphenous artery were 5.50+/-0.11 and 7.12+/-0.18, respectively. These results indicate that TA-993 shares a common profile with l-cis-diltiazem, and suggest that 1,5-benzothiazepine derivatives of a l-cis configuration are a different class of drug from that of the d-cis configuration.
Kaburaki
M
M
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Inoue
H
H
Doi
H
H
Yasuhara
M
M
Narita
H
H
D000758:Anesthesia; D000818:Animals; D001158:Arteries / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects
D002121:Calcium Channel Blockers; D010975:Platelet Aggregation Inhibitors; C097363:TA 993; D004110:Diltiazem